Persistence and Effectiveness of Nonbiologic Systemic Therapies for Moderate-to-Severe Psoriasis in Adults

A Systematic Review

K.J. Mason; S. Williams; Z.Z.N. Yiu; K. McElhone; D.M. Ashcroft; C.E. Kleyn; Z.K. Jabbar-Lopez; C.M. Owen; N.J. Reynolds; C.H. Smith; N. Wilson; R.B. Warren; C.E.M. Griffiths

Disclosures

The British Journal of Dermatology. 2019;181(2):256-264. 

In This Article

Abstract and Introduction

Abstract

Background: The persistence and effectiveness of systemic therapies for moderate-to-severe psoriasis in current clinical practice are poorly characterized.

Objectives: To systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate-to-severe psoriasis, exposed to therapy for ≥ 3 months.

Methods: MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow-up) or effectiveness [improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA)]. This review was registered with PROSPERO, number CRD42018099771.

Results: Of 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta-analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow-up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE-exposed patients achieved a markedly improved or clear PGA.

Conclusions: The comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real-world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used.

Introduction

Psoriasis is a chronic inflammatory skin disorder that impairs both physical and psychological health.[1] Treatment options for patients with psoriasis depend on disease severity, comorbidities and patient choice and include topical, phototherapy and systemic therapies (including biologics and small molecules).[2,3] More severe psoriasis frequently requires lifelong management, and therefore counselling patients on the likelihood of medium-to-long-term disease control is important when discussing treatment choice.

In the U.K., guidance provided by the National Institute for Health and Care Excellence (NICE) suggests the use of nonbiologic, nonsmall-molecule systemic therapies for the treatment of moderate-to-severe psoriasis that cannot be controlled with topical or phototherapies.[3] Methotrexate is recommended as first-line therapy, with ciclosporin advised in the short term and for women considering conception. Acitretin may be considered if methotrexate and ciclosporin are contraindicated or ineffective.[3]

Most of the available evidence related to systemic therapies is derived from randomized controlled trials (RCTs). These remain the gold standard for investigating new therapies, as participant randomization to receive active or comparator treatments and high internal validity facilitate causal inference of the efficacy and/or safety of the therapy under investigation between the trial arms. However, most RCTs are not fully representative of real-world clinical practice and are powered for efficacy outcomes rather than safety. Due to their relatively small sample sizes, short follow-up periods and strict inclusion criteria, RCTs may have low external validity.

Two studies have demonstrated that patients with psoriasis identified as ineligible for biologics RCTs are at least twice as likely as eligible patients to experience serious adverse events.[4,5] Attrition with longer-term RCTs or open-label extension studies may render the interpretation of safety data difficult due to the resulting bias in the sample studied. Postmarketing observational research is complementary to prelicensing trials to enable the exploration of the persistence (duration of time from initiating to discontinuing therapy)[6] and effectiveness (response to therapy observed within real-world conditions accounting for factors that may influence the therapy's performance)[7] of psoriasis therapies in clinical practice. Discontinuation of systemic therapy is common in clinical practice, hence long-term data collection is critical to investigating therapeutic outcomes.[8,9] The British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) is a well-established prospective pharmacovigilance register of patients diagnosed with psoriasis and treated with all forms of systemic therapy.[10] Observational data collected by registers such as BADBIR will provide important evidence for the persistence and effectiveness of systemic psoriasis therapies in real-world clinical practice.

We conducted a systematic review of the persistence and effectiveness of four commonly used nonbiologic, nonsmall-molecule systemic psoriasis therapies in observational studies over the past decade. The aim was to summarize and evaluate observational studies (involving ≥ 100 patients) investigating the persistence and/or effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) or methotrexate in adult patients with moderate-to-severe psoriasis.

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